The present invention relates to a novel thrombolytic, processes for its isolation, and its pharmaceutical usage.
Thromboses are produced by the formation of a blood clot in blood vessels. One distinguishes between venous thromboses including pulmonary embolisms and arterial thromboses including acute myocardial infarction.
Pulmonary embolism and cardiac infarction are life-threatening events requiring immediate medical intervention.
Besides various invasive methods, a popular form of therapy for arterial and venous thromboses has evolved in recent years in the form of enzymatic thrombolysis with plasminogen activators. These substances, called thrombolytics, convert plasminogen, the inactive proenzyme of the fibrinolysis system in the blood, into the active proteolytic enzyme,plasmin. Plasmin, in turn, dissolves the fibrous substance, fibrin, which is a substantial component of a blood clot; this leads to reopening of the blocked vessels and restoration of blood flow. However, plasmin is a relatively unspecific protease, i.e. once formed in the blood, it destroys,.by proteolysis, components in the blood indispensable for intact hemostasis (e.g. fibrinogen) and thereby induces under certain circumstances dangerous risks of hemorrhaging.
The thrombolytics of the first generation, streptokinase and urokinase, are compounds which, once injected into the circulation, systemically convert plasminogen into plasmin and induce systemic proteolysis. Therefore, thrombolysis therapies with these substances are frequently accompanied by complications due to hemorrhage. The fibrin-specific thrombolysis, developed thereafter, wherein recombined plasminogen activators of the tissue type, called t-PA for the sake of brevity, are employed, was supposed to lead out of this dilemma. In the blood circulation, t-PA has an only low affinity to plasminogen. However, in the presence of the fibrous substance, fibrin, with which it reacts by way of specific binding sites, this affinity is increased by a multiple, resulting in plasmin formation on the surface of the thrombus. This concept could be verified in vitro and in animal experiments; the clinical studies, however, show that large amounts of t-PA are needed in order to bring about rapid dissolution of a coronary thrombosis.
However, if doses of t-PA of such magnitude are infused, this will lead to a systemic proteolysis accompanied by a relative risk of hemorrhaging, in a similar way as in the cases of streptokinase and urokinase. Therefore, one speaks nowadays of a relative fibrin specificity of t-PA. The cause therefor lies in an essential characteristic of t-PA: This molecule is an active protease which, under favorable conditions (high enzyme concentration, long exposure time, high substrate concentration, optimal pH and ion environment), will convert plasminogen into plasmin even in the absence of fibrin. All of these conditions are met in present clinical standard therapy with t-PA.